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Neural Predictors and RAS Modulation of Radiation-induced Cognitive Impairment

辐射引起的认知障碍的神经预测因子和 RAS 调节

基本信息

批准号：
7822916
负责人：
MICHAEL E. ROBBINS
金额：
$ 24.73万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-14 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822916
关键词：
Acute Address Aging Angiotensin II Angiotensin II Type 1 Receptor Blockers Angiotensin-Converting Enzyme Inhibitors Animals Area Brain Brain Injuries Cognition Cognitive Cranial Irradiation Demyelinations Deterioration Dose Goals Grant Growth Growth Factor Human Impaired cognition Incidence Injury Insulin-Like Growth Factor I Intervention Kidney Lead Long-Term Survivors Lung Malignant Neoplasms Malignant neoplasm of lung Metastatic malignant neoplasm to brain Microscopic Modification Molecular Myelin Necrosis Neoplasm Metastasis Nerve Growth Factors Neurobiology Neurons Pathology Patients Performance Persons Primary Brain Neoplasms Process Production Public Health Publishing Quality of life Radiation Radiation-Induced Change Rattus Renin-Angiotensin System Reporting Research Personnel Residual Tumors Structure Synapses Testing Time age related clinically relevant cognitive change cognitive function improved malignant breast neoplasm melanoma middle age neoplastic cell oxidative damage prevent programs relating to nervous system response white matter white matter change young adult

项目摘要

DESCRIPTION (provided by applicant): Every year as many as 200,000 patients receive whole brain irradiation (WBI). Most of these patients are treated not for primary brain tumors, but for brain metastases from melanomas, breast cancer or lung cancer that increase in middle age. As patient survival after WBI has increased, 20-50% of the long term survivors develop radiation-induced brain injury, including cognitive impairment. Radiation-induced cognitive impairment occurs in the absence of gross structural pathology, suggesting that this phenomenon is likely preceded by subtle changes in the myelin or the synaptic connections among neurons that underlie cognitive function. However, there have been, i] no quantitative studies of radiation-induced changes in myelin and synapses, ii] no published studies of radiation-induced cognitive impairment with a clinically relevant fractionated course of radiation, and iii] no attempts to ameliorate or prevent this radiation-induced structural or cognitive damage in middle-aged animals. The overall goal of the present grant is to answer the following questions. What changes in myelin and synapses occur when middle-aged rats are given a clinically relevant dose of fractionated WBI? Are the subtle changes in myelin and synapses early predictors of the ensuing radiation-induced cognitive impairment? Will modulation of the intrinsic brain renin-angiotensin system (RAS) ameliorate or prevent this radiation-induced brain injury, including cognitive impairment? Accordingly, the hypotheses to be tested are that, 1) modifications in myelin and synapses are early predictors of radiation-induced brain injury associated with cognitive impairment, and 2) both the structural modifications and the cognitive impairment induced by WBI can be ameliorated or prevented by modulating the intrinsic brain RAS. To test these hypotheses, we will, i] quantify the changes in myelin, synapses and cognition after treating 12 month old F344XBN rats with a clinically relevant course of WBI, and ii] determine if inhibition of the intrinsic brain RAS by administration of ACE inhibitors or Ang II type 1 receptor antagonists will modulate the structural and/or cognitive damage after 12 month old F344XBN rats are treated with fractionated WBI. These studies should provide information that is likely to lead to treatments that ameliorate radiation-induced brain injury, including cognitive impairment; thereby, addressing one of NCI's new areas of public health emphasis.

描述（由申请人提供）：每年有多达200，000名患者接受全脑照射（WBI）。这些患者中的大多数不是因为原发性脑肿瘤而接受治疗，而是因为黑色素瘤、乳腺癌或肺癌在中年时增加的脑转移。随着WBI后患者存活率的增加，20-50%的长期存活者会出现辐射诱导的脑损伤，包括认知障碍。辐射诱导的认知障碍发生在没有总体结构病理学的情况下，这表明这种现象可能是由髓鞘或神经元之间的突触连接的微妙变化，认知功能的基础。然而，i）没有对髓鞘和突触中辐射诱导的变化进行定量研究，ii）没有发表关于具有临床相关分次辐射过程的辐射诱导的认知损害的研究，iii）没有尝试改善或预防中年动物中这种辐射诱导的结构或认知损害。本次赠款的总体目标是回答以下问题。当给予中年大鼠临床相关剂量的分次WBI时，髓鞘和突触发生了什么变化？髓鞘和突触的微妙变化是否是随后辐射诱导的认知障碍的早期预测因素？调节内源性脑肾素-血管紧张素系统（RAS）是否能改善或预防辐射诱导的脑损伤，包括认知障碍？因此，需要检验的假设是：1）髓鞘和突触的修饰是与认知障碍相关的辐射诱导脑损伤的早期预测因素，以及2）WBI诱导的结构修饰和认知障碍都可以通过调节来改善或预防大脑内在的RAS。为了测试这些假设，我们将：i）用临床相关的WBI过程处理12个月大的F344 XBN大鼠后，量化髓鞘、突触和认知的变化，和ii]确定通过施用ACE抑制剂或Ang II 1型受体拮抗剂来抑制内源性脑RAS是否将调节结构和/或功能。或在用分次WBI处理12月龄F344 XBN大鼠后的认知损伤。这些研究应该提供的信息，可能导致治疗，改善辐射引起的脑损伤，包括认知障碍，从而解决NCI的公共卫生重点的新领域之一。